RNA-Seq in 296 phased trios provides a high resolution map of genomic imprinting

Combining allelic analysis of RNA-Seq data with phased genotypes in family trios provides a powerful method to detect parent-of-origin biases in gene expression. We report findings in 296 family trios from two large studies: 165 lymphoblastoid cell lines from the 1000 Genomes Project, and 131 blood samples from the Genome of the Netherlands participants (GoNL). Based on parental haplotypes we identified >2.8 million transcribed heterozygous SNVs phased for parental origin, and developed a robust statistical framework for measuring allelic expression. We identified a total of 45 imprinted genes and one imprinted unannotated transcript, 17 of which have not previously been reported as showing parental expression bias. Multiple novel imprinted transcripts showing incomplete parental expression bias were located adjacent to known strongly imprinted genes. For example, PXDC1, a gene which lies adjacent to the paternally-expressed gene FAM50B, shows a 2:1 paternal expression bias. Other novel imprinted genes had promoter regions that coincide with sites of parentally-biased DNA methylation identified in blood from uniparental disomy (UPD) samples, thus providing independent validation of our results. Using the stranded nature of the RNA-Seq data in LCLs we identified multiple loci with overlapping sense/antisense transcripts, of which one is expressed paternally and the other maternally. Using a sliding window approach, we searched for imprinted expression across the entire genome, identifying a novel imprinted putative lncRNA in 13q21.2. Our methods and data provide a robust and high resolution map of imprinted gene expression in the human genome.